NO810064L - PROCEDURE FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE PYRIMIDINE-2-SULPHIDES AND S-OXIDES THEREOF - Google Patents

Abstract

Compounds of the formula <IMAGE> I (wherein X represents a halogen atom; n is 0, 1 or 2; R1 and R2, which may be the same or different, each represents a hydrogen atom or a carboxyl, esterified carboxyl, amido or mono- or di-C1-4 alkylamido group or a C1-4 alkyl group which may if desired carry a carboxyl or esterified carboxyl group; and R3 represents a C1-32 saturated or unsaturated, straight or branched, cyclic or acyclic aliphatic group or an araliphatic or heterocyclic substituted aliphatic group, a heterocyclic group or an aryl group which groups may if desired carry one or more substituents selected from halogen atoms and oxo, nitro, hydroxy, etherified hydroxy, esterified hydroxy, primary, secondary or tertiary amino, acylamino etherified mercapto or S=O or -SO2 derivatives thereof and esterified phosphonic acid groups) and, where an acidic or basic group is present, physiologically compatible salts thereof have been found to be of use in combating abnormal cell proliferation. The compounds are prepared inter alia by oxidation of the corresponding sulfide, displacement of a leaving atom or group from the 2-position of the pyrimidine by reaction with a sulfinic acid or by ring closure of the pyrimidine ring.

Description

This invention relates to the production of new pyrimidine-2-sulphides and their S-oxides which have interesting physiological activity and can therefore be used as pharmaceuticals.

Abnormal cell growth is the root cause of a number of diseases

such as cancer, leukaemia, cutaneous cell growth, e.g. contact dermatitis or psoriasis, or auto-immune diseases where lymphocyte growth leads to an unwanted immune reaction against some of the normal tissues in the body.

It has now been found that compounds with the formula:

where X means a halogen atom;

n is 0, 1 or 2;

12

R and R , which may be the same or different, each represent a hydrogen atom or a carboxyl, esterified carboxyl, amido

or mono- or di-C 4 alkylamido group or a C 4 alkyl group; and

R 3 means a C^_32 saturated or unsaturated, linear or branched, cyclic or acyclic aliphatic group or an araliphatic or heterocyclic substituted aliphatic group, a hetero-

cyclic group or an aryl group, which groups may optionally carry one or more substituents selected from halogen atoms and oxo, nitro, hydroxy groups, etherified hydroxy groups, esterified hydroxy groups, primary, secondary or tertiary amino groups, acylamino groups, etherified mercapto groups or

-SO- or -SC^ derivatives thereof, and esterified phosphonic acid groups,

and, when an acidic or basic group is present, the salts thereof,

has the ability to inhibit cell growth.

Abnormal cell growth can be combated by administration

of an agent that irreversibly affects cell division. Such agents are usually only able to attack the cells during a particular phase of the cell cycle, e.g. The S phase during which DNA is synthesized. Although the remedy cannot distinguish between

abnormal and normal cells that are in the phase that can be postponed

for attack, one can exploit the fact that a significant proportion of normal cells, which are important in this context (e.g. bone marrow) usually have a shorter cell cycle length than many abnormal cells, such as tumor cells, and thus regain their number more quickly . This effect is further promoted by the fact that usually a smaller proportion of normal cells will be in the cell cycle at the time the agent is administered, -compared to the situation in abnormal cells, and thus a larger supply is obtained from which cells can be taken to supplement normal cells which is destroyed by the agent.

The abnormal cells can therefore be reduced more easily by carefully timed stepwise administration of the agent.

Another way in which such an agent can be used to combat abnormal cell growth is to administer a preliminary agent that acts to reversibly arrest cell cycle division in a particular phase, e.g. metaphase, so that when the agent is removed from the system, all cells resume their division synchronously. However, the cell division cycle for the abnormal cells will usually be different from that found in the normal cells, and a time can be chosen when the abnormal cells can be exposed to attack by the irreversible agent, while the normal cells are in a resistant phase.

The compounds produced according to the invention inhibit DNA synthesis and are thus particularly useful in combating abnormal cell growth.

Appropriate pharmaceutical preparations may contain at least one compound produced according to the invention or, when an acidic or basic group is present, a physiologically compatible salt thereof, together with a pharmaceutical carrier or excipient.

The term "pharmaceutical preparation" is understood here to mean preparations both for administration to humans as well as to animals, and does not include simple solutions of the compounds of formula I in non-sterile water or an ordinary organic solution 1 .

The compositions may be prepared for pharmaceutical administration in any suitable manner. The preparations will thus normally be in a form suitable for oral, rectal, local or parenteral administration, such as tablets, coated tablets, capsules, granules, solutions, suppositories and creams for local treatment, ointments and liquids or sterile solutions in pyrogen-free water for injection or infusion. The preparations are normally administered in a daily dose in the range of 0.25 to 7.0 g of the compound prepared according to the invention, as the preparations will conveniently be prepared in unit doses, where each unit dose typically contains from 50 mg to 1.0 g of the compound, although units containing as much as 5 g may occasionally be appropriate.

Suitable carriers and auxiliaries can be used, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, animal and vegetable fats, paraffin derivatives, glycols, propellants and various wetting agents, dispersants, emulsifiers, flavorings and preservatives.

DNA synthesis in the cells of a host animal can be inhibited by

that said host animal is administered an effective amount of a compound prepared according to the invention or, when an acidic or basic group is present, a physiologically compatible salt thereof.

In particular, the compounds can be used to combat abnormal cell growth.

Certain of the compounds of formula I are described generally in Belgian patent 847,234 as intermediates, without any indication of physiological activity and without any particular compounds being mentioned. Furthermore, 5-chloro- and 5-bromo-2-methanesulfonylpyrimidine and their 4-carboxy derivatives and 5-fluoro-2-methanesulfonylpyrimidine are particularly described in Budesinsky Z

and Vavrina J. Collect. Czech Chem. Commun. 3_7 (1972) 172.1,

but again nothing is stated about the compounds' physiological activity.

As a result, this applies to the compounds of formula I

with the proviso that R 3 is not an unsubstituted alkyl, aralkyl or aryl group other than a phenyl or benzyl group when R and/or R is hydrogen or a C,_. alkyl group and X means a fluorine, chlorine or bromine atom and R 3 is different

1 2

from a methyl group when R is a carboxyl group, R is a hydrogen atom and X is a chlorine or bromine atom. In the new compounds of formula I can e.g. R 3 thus means a phenyl or benzyl group or a substituted alkyl, aralkyl or

aryl group or a heterocyclic or heterocyclic substituted aliphatic group when X represents a fluorine, chlorine or bromine atom. All the compounds of formula I where X is iodine are

new connections.

The terms used above in the definitions of

the compounds of formula I are discussed in more detail below.

The term "aliphatic" includes as preferred groups C 1 -g , especially alkyl, alkenyl or alkynyl groups, which may carry one or more substituents such as halogen, e.g. chlorine or iodine, pkso, amino, hydroxy, heterocyclic, etherified hydroxy, etherified mercapto, esterified hydroxy or mercapto groups. The term "aliphatic" also includes such radicals which contain C^-S cycloalkyl or alkenyl groups, which groups may possibly carry fused rings.

It will be understood that when an oxo group is located on a carbon atom bearing an amino, mono- or di-alkylamino, hydroxy or etherified hydroxy group, a carbonyl function such as a carbamoyl, mono- or di- alkylcarbamoyl, ureido, carboxy or esterified carboxy group. Such carbonyl sulfonic ions can be substituents on.

3 3

R -groups or can be the group R itself as in carbamoylthio groups.

The term "heterocyclic" here preferably refers to groups with 3 to 9, suitably 5 to 7, members in the ring and one or more heteroatoms selected from oxygen, nitrogen or sulfur and optionally with a fused ring or with one or more hydrocarbon substituents such as aliphatic groups, e.g. C 1-4 alkyl groups, aromatic rings such as phenyl groups or other heterocyclic rings. The ring system can be saturated or unsaturated, e.g. aromatic. Examples of such groups include thienyl, furyl, 2,4-dihydro-1H-1,4-diazepinyl, epoxy, azetidinone, perhydroazocinyl and pyrimidinyl groups which are optionally substituted with halogen, e.g. chlorine. The term covers, among other things, to saccharide residues, i.e. glycosyl groups, e.g. furanosyl and pyranosyl derivatives, e.g. glucofuranosyl or glucopyranosyl derivatives, including deoxy derivatives thereof, whose hydroxy groups may optionally be esterified, as in 2,3,4,6-tetra-0-acetylglucopyranosyl or 2,3,5-tri-0-benzoyl-(3-D -ribof uranosyl.

The term "aryl" refers here e.g. to aromatic ring systems with up to 10 carbon atoms, e.g. phenyl or naphthyl which is optionally substituted as indicated above, so

as a phenyl or p-chlorophenyl group. The designation "aryl"

shall also be understood to include aromatic ring systems which are substituted with an aliphatic group such as an alkyl group, e.g. with 1 to 4 carbon atoms, such as a p-tolyl group, or another aromatic ring such as phenyl, such as in a diphenyl group.

1 2

Preferably, only one of R and R is different from hydrogen or C,. alkyl, at least one preferably being

12

hydrogen. It is particularly preferred that both R and R are hydrogen.

1 2

When R and/or R is esterified carboxyl, it is preferably C₁₋₄ alkoxycarbonyl.

The term "araliphatic" refers here e.g. to aralkyl groups with up to 4 carbon atoms in the aliphatic part, optionally substituted in the aryl ring as indicated above. The aliphatic part can be unsaturated and can carry one or more substituents, e.g. an oxo group.

Examples of such araliphatic groups thus include

benzyl, phenethyl, trityl, styryl and. phenacyl.

R 3 in the compounds of formula I means e.g. a group or radicals bearing one or more etherified hydroxy groups or etherified mercapto or SO or SO2 derivatives thereof. The preferred hydroxy and mercapto substituents as well as the SO and SO 2 -derivative substituents are e.g. aliphatic, araliphatic, heterocyclic or aryl, -O-, -S- or -S02_groups (wherein the designations aliphatic, araliphatic, heterocyclic and aryl are as indicated above), suitably -O-aryl, -S-aryl, -S02~aryl , an -O-heterocyclic, -S-heterocyclic or -SO 2 -heterocyclic group, e.g. phenoxy, pyrimidinyloxy, pyrimidine-2-thio and pyrimidine-2-sulfone. It will be understood that the above-mentioned substituent groups may themselves be substituted as indicated above. Thus, e.g. substituents include halogen-substituted-O-aryl-, -S-aryl-, -SO2~aryl-, -O-heterocyclic, -S-heterocyclic and -SO2_heterocyclic, e.g. p-chloro-phenoxy-, 5-chloropyrimidin-2-yloxy-, 5-chloropyrimidin-2-yl-mercapto- and 5-chloropyrimidin-2-yl-sulfone groups.

When R bears an esterified hydroxyl or mercapto group, the esterifying group may be derived from an aliphatic>araliphatic, heterocyclic or aromatic carboxylic acid, e.g. a ^ 2-5 alkanoic acid such as acetic acid, or a C__, , aromatic acid such as benzoic acid.

When R 3 contains an esterified carboxyl substituent or is itself such a substituent (namely a C alkyl group bearing both an oxo group and an esterified hydroxyl group), the esterifying group can be an aliphatic, araliphatic, heterocyclic or aryl group as defined above, e.g. e.g. in the group 2-thienylmethoxycarbonyl-methylthio.

Esterified phosphonic acid groups as substituents in R 3 include e.g. di-(C-1-8 alkyl)-phosphate groups, in particular

di-(C, . alkyl) phosphonate groups such as diethyl phosphonate.

R 3 in the compounds of formula I as defined above can e.g. also mean a group or a radical which can be one or more primary, secondary or tertiary amino groups or acylamino groups, e.g. alkanoylamino groups.

Substituents on secondary and tertiary amino groups can e.g. be C^_^alkyl-, Cg_^Qaralkyl- or aryl groups or heterocyclic groups with 5 to 10 members in the ring, e.g. as defined above, and examples are methyl, ethyl, phenyl and tolyl.

Compounds of formula I containing solubilizing groups are of particular interest. Such compounds include e.g. polyhydroxy-containing groups such as groups derived from carbohydrates, amino acids, hydroxy acids and phosphorus-containing organic groups, e.g. phosphoric acid derivatives, as well as basic heterocyclic rings such as the 2,4-dihydro-1H-1,4-diazepinyl group.

The radical X in the compounds of formula I can be fluorine,

chlorine, bromine or iodine.

Compounds of formula I where n is 1 or 2 are preferred,

since the sulfones are somewhat more active than the sulfoxides.

Certain of the compounds of formula I may exist in salt form. When acidic groups are present in the compounds of formula I, salts can be formed with alkali metals or alkaline earth metals, e.g. sodium, potassium, magnesium or calcium or ammonium salts (including substituted ammonium). Compounds of formula I bearing basic groups, e.g. hydroxy or amino groups, usually have improved water solubility, and the latter of course also form acid addition salts, e.g. with mineral acids such as hydrochloric* or sulfuric acid, or organic acids such as acetic acid, tartaric acid or citric acid. However, nonionic compounds of formula I are usually preferred. It will be understood that the salts of the compounds of formula I for use in pharmaceutical preparations are the physiologically compatible salts. Other salts may, however, be useful in the preparation of the compounds of formula I and the physiologically compatible salts thereof. Preferred compounds of formula I, based on their activity, include compounds where R means a C^_^ alkyl or alkenyl group which may bear a halogen atom, a monocyclic, carbocyclic or heterocyclic aromatic ring or an optionally substituted pyrimidinyloxy group, e.g. e.g. a methyl group, a halomethyl group such as chloromethyl or iodomethyl, a methyl, ethyl or vinyl group bearing an acetyl group, or a monocyclic, carbocyclic or heterocyclic aromatic 5- or 6-membered ring, e.g. a phenyl or thienyl group or a methyl group bearing a 5-halopyrimidine-2-oxy group, e.g. a 5-chloropyrimidine-2-oxy group; or a salt thereof. In such compounds, ;12 ;n' is preferably 2, and R and R are preferably hydrogen. ;Compounds of formula I which are of particular interest;because of their physiological activity, also include the following compounds: 2-(chloromethyl)sulfonyl-5-chloropyrimidine, ;2-styrylsulfonyl-5-chloropyrimidine, ;2-benzylsulfonyl-5 -chloropyrimidine, ;2-( 3-oxobuten-1-yl)sulfonyl1-5-chloropyrimidine, ;2-(5-chloropyrimidine-2-oxymethyl)sulfonyl-5-chloropyrimidine, 2-(iodomethyl)sulfonyl1-5-chloropyrimidine, ;2-benzylsulfonyl-5-bromopyrimidine, ;2-benzylsulfinyl-5-chloropyrimidine and ;2-(2-thienylmethyl)sulfonyl-5-bromopyrimidine. It will be understood that certain of the compounds of formula I will exist in geometrically or optically active isomeric forms. The present invention includes the production of all these isomeric forms. According to the invention, the new compounds with formula I where n is 2 are produced by oxidation of a compound with the formula: 12 3 ;where R , R , R and X are as indicated above, and m is 0 or 1. ;The compound of formula I where n is 1 is preferably produced by oxidation of a corresponding compound of formula II (where m is 0, and R 1 , R 2 , R<3>and X are as indicated above), to form a compound of formula I where n is 1. The oxidation of a compound of formula II can be carried out by any convenient method , including the use of 1) a manganese-containing oxidizing agent, e.g. a permanganate, preferably potassium permanganate, suitably in the presence of an acid, e.g. acetic acid; 2) use of chlorine or a hypochlorite, e.g. sodium hypochlorite in an aqueous solution of the sulfide or sulfoxide; or 3) use of, a peroxide or a peracid oxidation system such as hydrogen peroxide, suitably in the presence of an acid, e.g. acetic acid, advantageously at ambient temperature, m-chloroperbenzoic acid is particularly preferred, preferably at a low temperature, e.g. at a temperature from -30 to -5°C, or using molybdenum peroxide, suitably in the presence of water and/or hexamethylene phosphoramide. In general, each oxidation method can be used to prepare either the sulfone or the sulfoxide, as the reaction conditions, e.g. the reaction time, temperature and excess of reagent, change depending on. the desired product. If it is thus desired to produce the sulfone, one can e.g. use a longer reaction time, higher temperatures and/or an excess of oxidizing agent. However, it is preferred to carry out the oxidation to the sulphoxide by e.g. to use 1) m-chloroperbenzoic acid, conveniently at a low temperature, e.g. at a temperature of -30 to -5°C, to avoid further oxidation to the sulfone; 2) hydrogen peroxide, suitably in the presence of an acid, e.g. acetic acid, advantageously at a low temperature, e.g. ambient temperature, avoiding excess of the oxidizing agent to reduce sulfone formation; and 3) hydrogen peroxide and selenium dioxide, advantageously under neutral conditions, suitably in the presence of a solvent, e.g. an alkanol such as methanol. These methods are preferred for sulfoxide formation because the oxidation reaction can be terminated more easily at the sulfoxide step. The course of oxidation can of course be monitored using chromatography. When it is desired to produce the sulfone, the oxidation can e.g. is carried out 1) using m-chloroperbenzoic acid, suitably in the presence of a solvent, e.g. dichloromethane, as the oxidation e.g. is carried out at a higher temperature than for the sulfoxide formation; 2) by using hydrogen peroxide, suitably in the presence of an acid, e.g. acetic acid, as the oxidation e.g. carried out in the presence of an excess of the oxidizing agent and/or at a higher temperature than for the sulfoxide formation; 3) when using chlorine, e.g. in aqueous solution, this method being preferred for sulfone formation especially when the sulfide (compound of formula II) is less easily oxidizable; 4) when using a manganese-containing oxidizing agent, e.g. potassium permanganate, suitably in the presence of an acid, e.g. acetic acid, this method also being preferred for the preparation of the sulfone because of the higher yields that can be obtained compared to milder oxidizing agents; and 5) using molybdenum peroxide, suitably in the presence of water and/or hexamethylphosphoramide, this method also being preferred for sulfone formation. A compound of formula I where n is 0 is first suitably prepared by condensation of a compound (where R 3 is as stated above) or an acid addition salt thereof, with a compound of the formula: ; 12 ; (where R , R and X are as stated above) or a functional derivative thereof such as an enol, enol ether, enol thioether, enamine or imine derivative, whereby a compound of formula I is obtained where n is 0. ; The condensation is conveniently carried out under acidic conditions, preferably in a solvent such as an alcohol, e.g. ethanol. When R 1 and R 2 each represent hydrogen, the reaction is conveniently carried out at ambient temperature. A functional derivative of a compound of formula IV can e.g. be formed by reacting both carbonyl groups in the compound of formula IV with a dialkylamine such as dimethylamine, and one of the thus formed imine groups can be rearranged in such a compound to the enamine form. The compound with formula I where n is 0 can e.g. also produced by a compound with the formula: ; 12 (where R , R and X are as indicated above, and Y means a leaving atom or group) is reacted with a thiol of the formula R 3SH or a thiolate of the formula ; (where R 3 is as stated above, M means the stabilizing cation and n means the cation's charge), whereby a compound of formula I is obtained where n is 0. The reaction of the compound of formula V with the compound of formula VI is conveniently carried out by using a compound of formula V where Y means a halogen atom, e.g. a chlorine or bromine atom. The reaction is a nucleophilic substitution reaction, the nucleophile being in the form R 3 S -, and when the compound of formula VI is used in the form of a thiol, the reaction is thus preferably carried out in the presence of a base which is sufficiently strong to remove the thiol proton for to form the above nucleophile. Preferred bases include alkoxides, e.g. alkali metal and alkaline earth metal alkoxides such as sodium or potassium alkoxides, e.g. ethoxides. The reaction is suitably carried out at an elevated temperature, preferably at the reflux temperature of the reaction mixture. The compound of formula II can e.g. also produced by a compound with the formula ; ; 12 ; (where R , R and X are as indicated above) is reacted with a reagent which serves to alkylate the sulfur atom to add a group ;3 3 ;R to it, e.g. an alcohol R Oll or an alkylating derivative thereof. Such an alkylating derivative can have the formula; ; (where R 3 and Y are as indicated above). The reaction is preferably carried out in the presence of a base or by means of phase-transfer catalysis, e.g. by using a triethyl-benzylammonium compound, e.g. the chloride, hereafter referred to as TEBA. Moreover, the reaction is preferably carried out using a compound of formula VIII where Y means a halogen atom, e.g. a chlorine or bromine atom. The reaction is suitably carried out at ambient temperature. The alkylating agent which is reacted with the compound of formula VII can also be an epoxide or azirane, and the product formed is then a 2'-hydroxy or 2'-amino alkylthio derivative, respectively. However, when the epoxide carries a leaving group such as a halogen atom adjacent to the epoxy group as in epichlorohydrin, the leaving group can then be removed along with the hydrogen atom in the hydroxyl group to form a further epoxide group. ;An alternative alkylating derivative is an acetal of the alcohol R 3OH, e.g. an acetal with a dialkylformamide such as dimethylformamide. The reaction of the alcohol R 3OH with the thione of formula VII requires the presence of a condensation catalyst, e.g. a di-t-alkyl acetal of a dialkyl formamide. The alkyl groups present in the dialkylformamide can have 1-5 carbon atoms, methyl being preferred. The t-alkyl groups are preferably neopentyl groups. The reaction is preferably carried out at an elevated temperature. When the compound of formula VII is reacted with a difunctional alkylating agent such as diiodomethane, dimeric compounds of formula II are formed where in reality R is an alkyl group bearing a 5-halo-pyrimidine-2-thio substituent, i.e. an etherified mercapto group . It has been found that oxidation of such a dimer by the methods described above can selectively convert only one of the S atoms into SO. We have also found that the above-mentioned dimeric compounds can be formed by heating a compound of formula II where R is a haloalkyl group, e.g. a chloromethyl group, with a base such as morpholine. Such compounds of formula I where n is 0 and R 3 is an alkyl group bearing a chlorine atom on the α-carbon atom, e.g. chloromethyl, can be prepared by reacting the corresponding alkyl derivative containing a cx-hydrogen atom with a chlorinating agent, e.g. sulfuryl chloride, e.g. at elevated temperature. Such haloalkyl derivatives can, as indicated above, serve as precursors for the production of Wittig reagents. When a corresponding compound is desired where R 3 is an alkyl group bearing a halogen atom other than chlorine, halogen exchange can be carried out, e.g. by reaction with an iodide or fluoride. According to a further feature of the invention, compounds of formula I where n is 0, 1 or 2 and R 3 means a vinyl group with the formula: 4 5 6 (where R , R and R , which may be the same or different, each means a hydrogen atom or a C 1-6 alkyl group, an aralkyl group, a heterocyclic alkyl group, an aryl group or a heterocyclic group, which groups may optionally be substituted as indicated above), is produced by a compound with the formula: 7 4 8 9 (where R means the group -CHR -P(0)R R or 4 8 9 10 where- R is as indicated above,, and R , R and R , which may be the same or different, each meaning an aryl or alkoxy group) is reacted with a compound of the formula ; (where R 5 and R 6 are as indicated above), whereby the desired vinyl derivative is obtained. ;The compound of formula IX is suitably prepared first by reacting a compound of formula I where R<3>means the group -CHR 4 Y- (where Y and R 4 are as indicated above, with a phosphine or phosphite, e.g. a triarylphosphine , eg triphenylphosphine or a trialkyl phosphite, eg triethyl phosphite. ;The vinylation reaction is suitably carried out under the conditions of a Wittig reaction or preferably a Horner-Wittig reaction. ;Vinylation can also be achieved by a compound of 12 ;formula VII (where R and R have the meanings given above); 4 _ 7 is reacted with an ethynyl compound with the formula R -C=C-R ; (where R 4 has the meaning given above and R 7 is preferably an acyl group, e.g. a lower alkanoyl (C 1 -g ) group such as an acetyl group or a carbonyl group or a derivative thereof such as an amide or ester group, wherein R<4> is preferably hydrogen). The reaction can be carried out in an inert solvent, e.g. a halogenated hydrocarbon such as chloroform. ;Compounds with formula I where R means a propargyl group can be prepared by the methods described above. ;Depending on the reaction conditions, however, the propargyl group can isomerize to form the corresponding propadienyl compound. The reaction product can thus be a propargyl compound, a propadienyl compound or a mixture of the isomers. When e.g. a propargyl sulfide of formula I is oxidized using p-chloroperbenzoic acid., the sulfide can be oxidized to the sulfone, the propargyl group isomerizing under the oxidation conditions to give the propadienyl isomer in high yield. When, on the other hand, selenium dioxide and hydrogen peroxide are used, the product is the propargylsulfinyl derivative. The compounds of formula I where n = 2 can also be prepared directly from compounds of formula V (where R 1 , R 2 , X and Y have the meanings given above) by reaction with a sulfinic acid of the formula R 3 SO 2 H or a salt thereof. When the acid is used, the reaction should be carried out in the presence of a base. The salt of sulfinic acid can e.g. be an alkali metal or alkaline earth metal salt or a salt of a tertiary organic base. The reaction can be carried out in a polar solvent such as an alkanol, e.g. methanol. A quaternary ammonium salt such as triethylbenzylammonium chloride may conveniently be present as a phase transfer catalyst for the salt, conveniently in the presence of lithium chloride. In the following, the turnover will be described in more detail in the examples which will serve to illustrate the invention in more detail. Many of the starting compounds are prepared according to previous publications, and references are given when applicable. ;Example 1 ;2-phenylthio-5-chloropyrimidine;A solution of thiophenol (60 mmol) in 0.43 M sodium ethoxide (150 ml) and a solution of 2,5-dichloro-pyrimidine ( ) in absolute ethanol (90 ml) was mixed and heated under reflux for 2 hours. The cold mixture was then filtered, the filtrate was evaporated, the remaining material was dissolved in chloroform (150 mL), the chloroform solution was washed with 2M NaOH (2 x 15 mL) and water (15 mL) and the dried (MgSO 4 ) the solution was evaporated to give an oily material which crystallized in the cold; yield 70%, sm.p. 47°C (naphtha). ;<1>H NMR (CDCl 3 ): δ 7.4 (Ph), 8.33 (H-4, H-6). ;Example 2;2-benzylthio-5-chloropyrimidine;Method A:;A solution of 5-chloropyrimidine-2-thione (4.6 mmol) and;2M NaOH (7 ml) was mixed with a solution of benzyl bromide ;(6 ;9 mmol) and triethylbenzylammonium chloride (TEBA; 4.6 mmol); in dichloromethane (20 mL). The two-phase system was vigorously stirred at room temperature for 16 hours, the layers were separated, the aqueous solution was extracted with dichloromethane, the dichloromethane solutions were combined and washed with water, and the dried (MgSO 4 ) solution was evaporated; dividend 46%. The crude product was sufficiently pure for the subsequent oxidation. <L>H NMR (CDCl-3): 6.4,45 (CH ) , 7.28 (Ph), 8.41 (H-4, H-6).-Method B: A solution of 1, 3-bis -TSI, N-dimethylamino-2-chlorotrimethinium perchlorate (38.3 mmol) and benzylisothiouronium chloride (40.7 mmol) were prepared in methanol (100 mL) and tert-BuOK (40.7 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 minutes after the addition was complete, after which additional tert-BuOK (38.3 mmol) was added and the mixture was heated under reflux for 2.5 hours. The precipitate was removed, the solvent was distilled from the filtrate, water (20 ml) was added to the residue, the aqueous solution was extracted with ether, the ether solution was dried (MgSO 4 ) and HCl gas was passed through the solution at 0°C. The precipitated salt is decomposed during drying, in vacuum and HC1 is released; dividend 43%, ;sm.p. 57°C (dilute MeOH). ; 1 H NMR (CDCl 3 ): δ 4.33 (CH 2 ), 7.26 (Ph), 8.40 (H-4, H-6). ;Example 3;2-phenylthio-5-bromopyrimidine;The title compound was prepared from 2-chloro-5-bromopyrimidine and thiophenol as described in Example 1, ;yield: 90% of a non-crystalline product which was sufficiently pure for the subsequent oxidation . ;MS m/e: 26 7 (M, 100%). 1 H NMR (CDCl 3 ): δ 7.4 (Ph), 8.50 (H-4, H-6). ;Example 4;2-allylthio-5-chloropyrimidine;Method A:;1,3-bis-N,N-dimethylamino-2-chlorotrimethinium perchlorate; (31 mmol). and 2-allylisothiouronium bromide (35 mmol) were dissolved in methanol and methanolic 1.67M sodium methoxide (35 mmol) was added. The mixture was stirred at room temperature for 30 minutes before an additional 19 mL of the sodium methoxide solution (31 mmol) was added. The mixture was then heated under reflux for 2.5 hours, the solvent was distilled off, water (100 ml) was added to the residue, the mixture was extracted with chloroform, the dried (MgSO 4 ) chloroform solution was evaporated and the residue was distilled; yield 86%, k.p. 62-64°C/0.1 -mm Hg. ;(<1>H NMR (CDCl3) : 6 3.76 (2 H-CHj.) 5.0-6.4 (3 H-vin.y 1) , 8.40 (H-4, H-6 ).;Method B:;5-Chloropyrimidine-2-thione (8 mmol) and N,N-dimethylformamide diallyl acetal (8 mL) were heated together in acetonitrile (40 mL) at 70°C for 90 min. The solvent was then distilled off, the residue was dissolved in ether (50 ml), the solution was extracted with 2M NaOH (2 x 50 ml), the ether solution was washed and dried (MgSO 4 ), the ether was evaporated and the residue was distilled; yield 74%, b.p. 62- 63°/0.1 mm Hg. ;Example 5:;2-benzylthio-5-chloropyrimidine;5-chloropyrimidine-2-thione (8 mmol) and N,N-dimethylformamide-dibenzyl acetal (8 mmol) were heated together. acetonitrile (40 mL) at 70° C. for 90 min. The solvent was then distilled off, the residue was dissolved in ether (50 mL), the ether solution was extracted with 2M NaOH (2x5 mL), washed with water (5 mL) and dried ( MgSO^) and gaseous HC1 was passed through the solution. The title compound was precipitated as the HCl salt; yield 80%. (Physical data: ;so m indicated in example 2). ;Example 6;Bis-(5-chloropyrimidin-2-ylthio)methane;Method I:;Methanolic 2M sodium methoxide (9 mmol) and diiodomethane;(20 mmol) were added to a solution of 5-chloropyrimidin-2-thione ( 9 mmol) in methanol (20 mL), and the mixture was stirred at room temperature for 2 h. The solid precipitate was collected, washed thoroughly with water and recrystallized from ethanol; yield 88%, sm.p. 162°C. ;(1H NMR (GDC13): δ 4.83 (CH2), 8.50 (4 H-4.6, s). ;Method II:;2-chloromethylthio-5-chloropyrridine (0.5 mmol) and morpholine ;(1 mL) were heated together in benzene (5 mL) overnight. ;A little precipitate was removed by filtration, and the filtrate was evaporated. The residue was washed with water and recrystallized from ethanol; yield 92%, physical data as above. ; Example 7: ;2-(chloromethyl)thio-5-chloropyrimidine;2-methylthio-5-chloropyrimidine;2-methylthio-5-chloropyrimidine;(75 mmol) and sulfuryl chloride;(104 mmol) were heated together in dichloromethane (100 ml) under reflux for 3 hours. Evaporation of the mixture gave a solid which was recrystallized from ethanol, yield 82%, mp 78° C. <1>H NMR (CDCl 3 ): 5.20 (SCH 2 ), 8.54 (H-4, H-6). ;Example 8;2-(iodomethyl)thio-5-chloropyrimidine;Sodium iodide (30 mmol) was added to a solution of 2-chloromethylthio-5-chloropyrimidine (6.7 mmol) in acetone (30 ml) , ;and the mixture was heated under reflux for 4 h. The precipitated sodium chloride was removed by filtration, the filtrate was evaporated to moisture and the residue was triturated with water and recrystallized from ethanol; yield 86%,;sm.p. 67°C. ; NMR (CDCl): 6 4 , 82 (SCH 2 ), 8.67 (H-4, H-6)'. ;Example 9 ;2-methylthio-4-methoxycarbonyl-5-chloropyrimidine ;A solution of 2-methylthio-4-carboxy-5-chloropyrimidine (31 mmol) in thionyl chloride (50 ml) was heated under reflux for 60 minutes .Excess thionyl chloride was distilled off, the remaining material was dissolved in methanol (70 mL), the solution was heated under reflux for 30 minutes, excess methanol was distilled off, the residue was dissolved in chloroform, the chloroform solution was washed with sodium bicarbonate and water, and the dried (MgSO 4 ) solution was evaporated and the residue distilled; yield 78%, mp 108-110°C/0.15 mm Hg. ; <X>H NMR (CDCl 3 ): δ 2.56 (SMe), 4.00 (OMe ), 8.63 (H-6). ;Example 10 ;2-methylthio-4-N,N-diethylaminocarbonyl-5-bromopyrimidine 2-methylthio-4-carboxy-5-bromopyrimidine (11 mmol) in ;thionyl chloride (25 ml) was heated under reflux for 70 minutes. Excess thionyl chloride was distilled off, the remaining material was dissolved in toluene, and a solution of diethylamine (22 mmol) in toluene (20 mL) was added dropwise with vigorous stirring. The mixture was heated at 90°C for 45 min, the solvent evaporated, the residue extracted with chloroform (100 mL), the chloroform solution washed (3 x 10 mL) and dried (MgSO 4 ), and the solution filtered through an alumina column (30 g, activity III). Evaporation of the chloroform eluate gave an oily substance which crystallized slowly; yield 74%, sm.p. 81°C (hexane). ;<1>H NMR (CDCl 3 ): 1.21 and 3.16/3.58 (NEt 2 ) 2.55 (SMe), ;8.63 (H-6). ;Example 11;Diethyl-(5-chloropyrimidine-2-thio)methanephosphonate ;2-(chloromethyl)thio-5-chloropyrimidine (20 mmol) and triethyl phosphite (15 ml) were heated together under reflux for 24 hours. The reaction mixture was then evaporated to dryness under reduced pressure, and the residue was purified by thick-layer chromatography; yield of crude product 3.39, sm.p. about 30°C. The product was used in the following step without further purification. 1:H NMR (CDCl 3 ): 1.29 and 4.12 (OEt), 3.54 (2 H-CH 2 ,; J p 14 Hz), 8.44 (H-4, H-6). MS [70 eV, m/e (% rel. int.)]: 296 (24, M), 160 (100). Example 12 2-(3-oxob. uthen-1-yl)thio-5-chloropyrimidine;3-butyn-2-one (5 mmol) in chloroform (25 ml) was added dropwise over 10 minutes at room temperature to a stirred suspension of 5-chloropyrimidine-2-thione (4.5 mmol) in chloroform (25 mL). The mixture was stirred for an additional 10 minutes before the solvent was evaporated. The residue was crystallized from methanol; yield 72%, sm.p. 89°C; NMR (CDCl 3 ) : 6 2.20 (Me-(Z ) ) , .2.23 (Me-(E)) , 6 .52 (Ha, d,;J 18 Hz (E)), 6.58 (Ha, d, J 10 Hz (Z)), 8.43 (H3, d,;J 10 Hz (Z)), 8.57 (HØ, d, J 18 Hz (E)), 8 .62 (H-4, H-6); ;(E)/(Z) = 1:1. IR (KBr): 1660 cm (CO). ;Example 13;2-(4-chlorophenoxymethyl)thio-5-chloropyrimidine;A mixture of p-chlorophenoxymethyl chloride (6 mmol) and the potassium salt of 5-chloropyrimidine-2-thione (5 mmol) in 1,2-dimethoxyethane (25 ml ) was stirred at room temperature for 10 hours, the solvent was distilled off under reduced pressure, the residue was extracted with chloroform (70 ml), the chloroform solution was washed with 1M NaOH (2 x 10 ml) and water (10 ml). and the dried (MgSO 4 ) solution was evaporated. The remaining sulfide was recrystallized from iPrOH; yield 70%, ;sm.p. 120°C. ;<1>H NMR (DMSO-dg): δ 5.90 (SCH 2 ), 6.98 and 7.31 (Ph), 8.78; (H-4, H-6). ;Example 14;2-(2-hydroxy-3-chloropropyl)thio-5-chloropyrimidine;A mixture of 5-chloropyrimidine-2-thione (14 mmol) and triethylamine (14 mmol) was stirred together in dichloromethane (30 ml ) for 5 min before epichlorohydrin (15 mmol) was added. The mixture was stirred at room temperature for 3 hours, the solvent was evaporated, the residue was triturated with water, the insoluble material was extracted with chloroform, the dried (M<g>SO^)chloroform solution was evaporated and the residue was crystallized from chloroform: petroleum ether; yield 30%, sm.p. 99°C. ;1H NMR (acetone-d6): 3.3-3.8 (2CH2, m) , 3.9-4.4 (CH, m) , 4.6-4.7 (OH), 8.59 (H-4, H-6). Example 15 2-propargylthio-5-chloropyrimidine A mixture of 5-chloropyrimidine-2-thione (5 mmol) and triethylamine (5 mmol) was stirred together in dichloromethane (40 mL) for 5 minutes before propargyl bromide (6 mmol ) was added. The mixture was stirred at room temperature for 1 hour before the solvent was evaporated. The residue was triturated with water (20 mL) and the solid was recrystallized from methanol; yield 87%, sm.p. 66 C. ;<1>H NMR (CDCl 3 ) : δ 2.16 (HC=, t., J 2Hz), 3.88 (CH 2 , d, J 2 Hz), 8.80 (H-4, H -6). IR (KBr) : 3300 cm"<1>(HC=). ;Example 16 ;2-( 2, 3, 4, 6- tetraacetylglucopyranosyl) thio-5-chloropyrimidine; A mixture of 5-chloropyrimidine-2-thione ( 10 mmol) and triethylamine (10 mmol) were stirred together in benzene (35 mL) for 30 minutes before a solution of tetraacetyl-1-bromoglucose (10 mmol) in benzene (15 mL) was added. The mixture was stirred at room temperature in 4 hours, the solid was removed and washed with chloroform, the combined chloroform washings and the benzene solution were evaporated, the residue triturated with water (20 mL) and the solid recrystallized from MeOH, yield 48%, mp 172° C. 1 H NMR (CDCl 3 ): δ 2.03 (Ac), 3.8-5.8 (glucose), 8.50 (H-4, H-6). ;Example 17 ;2-phenacylthio-5-bromopyrimidine;5-bromopyrimidin-2-thione (10.5 mmol) was added to a solution of triethylamine (11.6 mmol) in EtOH (130 ml) and the mixture was stirred for 15 minutes before adding phenacyl bromide (10.5 mmol). The reaction mixture was stirred for 1 hour before the solvent was removed under reduced pressure, the residue extracted with chloroform and the chloroform solution chromatographed on alumina (100 g, Activity I); yield 71%, sm.p. 107-109°C (iPrOH). ;"""H NMR (CDCl 3 ) : δ 4.60 (CH 2 ), 7.5-8.0 (Ph), 8.46 (H-4, H-6). ;Example 18; 2-(carbamoylmethyl ) thio- 4 > 6- dimethyl- 5- bromopyrimidine;a) 4, 6- dimethyl- 5- bromopyrimidin- 2- thione HC1:; A solution of 2-chloro-4,6-dimethyl-5-bromopyrimidine; (21 .7 mmol) and thiourea (21.8 mmol) in ethanol (100 mL); was heated under reflux for 5 hours. The solvent was distilled off, the residue was extracted with 1M NaOH (60 mL) under heating for 60 minutes, the mixture was filtered and the pH of the cold filtrate was adjusted to about 3 using HCl when the thiolactam had precipitated, yield 60%, m.p. 270°C (dec.) (aqueous EtOH). 1H NMR (TFA) : 6 2 , 83 (Me).;b) 2-(carbamoylmethyl)thio-4,6-dimethyl-5-bromopyrimidine 4,6-dimethyl-5-bromopyrimidine-2-thione HCl salt (5 mmol) was added to ethanolic (60 mL) KOH (11.4 mmol), the solution was stirred at room temperature for 10 minutes, iodoacetamide (5.7 mmol) was added, and stirring was continued for 20 minutes at room temperature and for 100 minutes at 70°C (pH 8). The hot reaction mixture was filtered, the filtrate evaporated, the residue extracted with chloroform (150 mL), the chloroform solution washed and the dried (MgSO 4 ) solution evaporated to give the sulfide; yield 72%, mp 175-177°C (iPrOH).<1>H NMR (DMSO-d,o .): δ 2.50 (Me), 3.80 (SCH 2„.). ;Example 19 ;2-(2-thienyl)thio-5-chloropyrimidine;2,5-dichloropyrimidine (11.3 mmol) was added to a solution of thiophene-2-thiol (12.3 mmol) in ethanolic ( 50 mL) ;0.246M NaOEt. The reaction mixture was stirred at room temperature for 15 minutes and heated under reflux for 2 hours. The solvent was then evaporated et, the residue extracted with chloroform, the chloroform solution washed with 2M NaOH and the dried (MgSO 4 ) solution evaporated to give the sulphide; yield 89%, sm.p. 65°C (petrol, b.p. 100°C). 1 H NMR (CDCl 3 ): δ 7.03, 7.26, 7.53 (thiophene), 8.40 (H-4, H-6). Example 20 2-(2-thienylmethylthio)-5-bromopyrimidine 2-bromomethylthiophene (15.2 mmol) was added to the potassium salt of 5-bromopyrimidin-2-one (12.6 mmol) in 1,2-dimethoxyethane (50 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure, the residue extracted with chloroform (70 ml), the chloroform solution washed with 1M NaOH (20 ml), water (2 x 10 ml) and the dried (MgSO 4 ) solution evaporated to give the sulphide; yield 77%, syrup. 87°C (iPrOH).;<:>H NMR (CDCl 3 ): δ 4.50 (CH 2 ), 6.90 (H-3<*>, H-4'), 7.13 (H-5" ), 8.50 (H-4, H-6).

Example 21

2- benzylthio- 5- bromopyrimidine

Benzylthiol (22 mmol) was added to 0.146M ethanolic NaOEt (150 mL) at room temperature, followed by 2-chloro-5-bromopyrimidine (20 mmol). The mixture was stirred at room temperature for 70 min and heated under reflux for 40 min, the solvent was evaporated under reduced pressure, the residue was extracted with chloroform (100 ml), the chloroform solution was washed with 2M NaOH and the dried (MgSO 4 ) solution was evaporated; yield 81%, sm.p. 68-69°C (dilute MeOH).

"""H NMR (CDCl 3 ): δ 4 , 36 (CH 2 ), 7.26 (Ph), 8.50 (H-4, H-6).

Example 22

2- benzylthio- 4, 6- dimethyl- 5- bromopyrimidine

2-Chloro-4,6-dimethyl-5-bromopyrimidine (10 mmol) was added to a solution of benzylthiol (11 mmol) and 0.138 M NaOEt in ethanol (80 mL). The mixture was stirred at room temperature for 70 minutes and then heated under reflux

for 40 minutes. The solvent was then distilled off, the residue was extracted with chloroform (50 ml), the chloroform solution was washed with 2M NaOH and the dried (MgSO 4 ) solution was evaporated to give the sulphide which was purified by distillation; yield 94%, k.p. 232-234°C/15 mm Hg.

1 H NMR (Cl 3 CF): 6 2 , 50 (Me-4., Me-6), 4.26 (CH 1 ), 7.20 (Ph).

Example 23

2-(4-chlorophenoxymethyl)thio-5-chloropyrimidine

2-(Iodomethyl)thio-5-chloropyrimidine was added to a solution of p-chlorophenol (5.5 mmol) and 0.138 M NaOEt in ethanol (40 mL) and the mixture was stirred at room temperature. The solvent was distilled off, and the mixture was worked up as above; dividend 64%.

Example 2 4

. 2-(5-chloropyrimidine-2-oxymethyl)thio-5-chloropyrimidine and 2-(5-chloropyrimidine-2-one-1-ylmethyl)thio-5-chloropyrimidine

2-(Iodomethyl)thio-5-chloropyrimidine (15.6 mmol) in DMF (20 mL) was added to the potassium salt of 5-chloropyrimidin-2-one (15.0 mmol) in DMF (60 mL). The mixture was stirred at room temperature for 8 hours before the solvent was distilled off. The residue was triturated with water, and the insoluble N- and O-alkylated isomers were separated by fractional crystallization from acetone; 2-(5-chloropyrimidine-2-oxymethyl)thio-5-chloropyrimidine was the most soluble isomer; yield 36%, mp - 128°C (MeOH).

<1>H NMR (CDCl3): δ 6.15 (CH2), 8.48 (2H in pyrimidine), 8.51

(2H in pyrimidine).

The least soluble isomer in the acetone solution was 2-(5-chloropyrimidin-2-on-1-ylmethyl)thio-5-chloropyrimidine; yield 64%, sm.p. 210°C (acetone).

Calculated for CgH6Cl2N4OS: . C 37,38,. H 2.10.

Found: C 37.59, H 2.07.

■""H NMR (CDCl 3 ): δ 5.56 (CH 2 - ), 8.29 and 8.57 (H-4, H-6, J 3 Hz), 8.62 (H'-4, H' -6). IR (KBr) : 1670 (CO), MS (70 eV; m/e (% rel. int.)):288 (20, M) 159 (23), 149 (40), 147 (100),

143 (73) .

Example 2 5

2-propargylthio-5-chloropyrimidine and 2-(1,2-propadienyl)-thio-5-chloropyrimidine

a) S-propargyl isothiouronium bromide and S-(1,2-propadienyl)-i sothiouronium bromide

Thiourea and propargyl bromide were heated in ethanol as described for the synthesis of S-propargyl isothiouronium bromide (see Salo, K., Chem. Abst. 51 (1957) 17760d) and instead gave a mixture of the isomeric title compounds in the ratio 1:1.. "■ "H NMR (D 2 Q: δ 2.90 (S-CH 2 C = CH, t, J 2 Hz) and 4.05

(S-CH2C = CH, d, J 2 Hz), 5.35 (S-CH=C=CH_2, d, J 6 Hz) and 6.08 (S-CH-C=CH2, t, J 6 Hz ).

b) 2-propargylthio-5-chloropyrimidine and 2-(1,2-propadienyl)-thio-5-chloropyrimidine

Methanolic sodium methoxide (84 mmol) was added to a solution of 1,3-bis-N,N-dimethylamino-2-chlorotrimethinium perchlorate (40 mmol) and the 1:1 isothiouronium bromides (44 mmol) in methanol (100 ml),' and the mixture was heated under reflux for 30 minutes. The solvent was then distilled off, the residue was triturated with water and dried. The spectra showed that the product was a mixture of the title compound,

in the ratio 3:1 (1H NMR); dividend 48%.

Example 2 6

2-(2,3-epoxypropyl)thio-5-chloropyrimidine

A mixture of 5-chloropyrimidine-2-thione (6.9 mmol) and potassium tert-butoxide (6.9 mmol) was stirred together in aq.

free DMF (40 mL) for 5 min before epiiodohydrin (6.9 mmol)

was added. The mixture was stirred at 80°C for 7 hours while small portions of potassium tert-butoxide were added from time to time to maintain a strongly basic solution. The solvent was then removed under reduced pressure, the residue was triturated with water (50 mL), the insoluble material was extracted with chloroform and the dried (MgSO 4 ) chloroform solution was evaporated to give the oily sulfide, yield 29%. . This material was chromatographically homogeneous and was identified by its spectroscopic properties.

<1>H NMR (CDCl 3 ): δ 2.6-3.4 (5 H, m), 8.50 (H-4, H-6).

Example 2 7

2-(5-nitro-2-thienyl)thio-5-chloropyrimidine

A mixture of 5-chloropyrimidine-2-thione (7.5 mmol), triethylamine (9 mmol) and 2-bromo-5-nitrothiophene (9 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2 days. The resulting solution was then diluted with dichloromethane (50 mL), the solution was shaken with 1M NaOH (2 x 10 mL) and then with water (10 mL), the dried (MgSO 4 ) solution was evaporated and the solid residue recrystallized from petroleum ether , yield 63%, m.p.'141-143°C.

"""H NMR (CDCl ) : δ 7.16 and 7.83 (H-3<1>, H-4<1>), 8.53 (H-4, H-6).

Example 2 8

2-[N-(2-tolyl)carbamoylmethyl)thio-4,6-dimethyl-5-bromopyrimidine

a) N-(iodoacetyl)-2-toluidine

A mixture of N-(bromoacetyl)-2-toluidine (0.16 mmol) and

Kl (0.32 mmol) in methanol (270 mL) was heated under reflux for 2.5 h. The cold reaction mixture was poured into water (2 L), and the precipitated iodide was dried;

yield 82%, sm.p. 145-146°C (MeOH).

1 H NMR (TFA) : δ 1.79 (Me), 3.61 (CH 2 ), 6.8 (Ph).

b) 2-[N-(2-tolyl)carbamoylmethyl)thio-4,6-dimethyl-5-bromo-. pyrimidine

N-(iodoacetyl)-2-toluidine (11.4 mmol) was added to a solution prepared from 4,6-dimethyl-5-bromopyridine-2-thione-HCl

(10 mmol) and KOH (22.8 mmol) in ethanol (140 mL). The resulting mixture was stirred at room temperature for 20 minutes and then at 70°C for 3 hours (pH 8). The hot reaction mixture was then filtered, the filtrate was evaporated and the residue extracted with chloroform (200 ml), the chloroform solution was shaken with water and the dried (MgSO 4 ) solution was evaporated; yield 80%, sm.p. 168°C (MeOH).

Example 29

. 2- phenylthio- 5- fluoropyrimidine

A solution of 2-chloro-5-fluoropyrimidine (10 mmol) in

ethanol (15 mL) was added dropwise over 5 minutes to a solution prepared from thiophenol (10 mmol) and 0.43M NaOEt in ethanol (25 mL). Then the mixture was heated to boiling, and refluxed for 2 hours, the mixture was filtered while hot, the filtrate was evaporated, the residue was extracted with chloroform (50 mL), the chloroform solution was shaken with 2M NaOH (2 x 10 mL) and then with water (10 mL) and the solution was evaporated; yield 69%.

1 H NMR (CDCl 3 ): δ 7.4 (pyr), δ 8.23 (H-4, H-6).

Example 30

2-(4-azetidin-2-one)thio-5-chloropyrimidine

5-chloropyrimidine-2-thione (3 mmol) was added to a

solution of potassium tert-butoxide (3 mmol) in DMF (10 mL) and the mixture was stirred for 10 min before a solution of 4-acetoxyazetidin-2-one (3 mmol) in DMF (10 mL) was added.

The resulting solution was stirred at room temperature i

36 hours, the solvent was removed under reduced pressure, the residue was triturated with hexane, the residue was dissolved in

water, the water solution was repeatedly extracted with ethyl acetate, and the dried (MgSO 4 ) ethyl acetate solution

was evaporated; yield 44%, sm.p. 181-182°C. EtOAc

1 h NMR (DMSO-do 1 ): δ 2.75-3.6 (CH Zn, m), 5.4 (CH), 8.7 (H-4, H-6).

Example 31

2- [ 3-( 1- perhydroazocinyl) propyl] thio- 5- chloropyrimidine

5-chloropyrimidine-2-thione (2 mmol) and potassium tert-butoxide

(2 mmol) were stirred together in DMF (20 mL) for 5 min at room temperature before 1-(3-chloropropyl)perhydroazocine (2 mmol) was added. The mixture was stirred for 2 days at room temperature and for 2 hours at 80°C. The solution was evaporated, the residue triturated with water and extracted with chloroform and the dried (MgSO 4 ) chloroform solution was evaporated. The oil

The remaining product (0.47 g) was the title compound; dividend 45%.

<1>H NMR (CDCl 3 ): 1.3-2.8 (9 x CH 2 , 3.20 (SCH 2 ) , 8 , 40 (H-4 , H-6). The compound was further characterized as a solid product

by conversion to its HCl salt using HCl in ethanol, m.p. 154°C (acetone).

Example 32

2-[N-(4-phenylazetidin-2-one)methyl]thio-6-chloropyrimidine Potassium tert-butoxide (2 mmol) was added to a solution

of 4-phenylazetidin-2-one (2 mmol) in DMF (25 mL) and the mixture was stirred for 5 min before 2-(iodomethyl)thio-5-chloropyrimidine

(2.0 mmol) in DMF solution (10 mL) was added. The mixture

was stirred at room temperature overnight, the solvent was distilled off under reduced pressure, the residue was triturated with water,

the insoluble material was dissolved in chloroform, the dried (MgSO 4 ) chloroform solution evaporated and the residue chromatographed on a silica gel column using chloroform; yield 33%, sm.p. 52°C.

<1>H NMR (CDCl3): δ 2.8-3.5 (CH2CO, m), 4.5-4.7 (CH), 4.6 and 5.2

(CH 2 , J 14 Hz), 7.3 (Ph), 8.2 (H-4, H-6). IR (CHC13):

1760 cm"<1>(CO).

Example 33

2- ( 2, 4- dihydro- 5( 7)- methyl- 7( 5)- phenyl- 1H- 1, 4- diazepin- 6- yl)- thio-5- chloropyrimidine• HCIO^

A solution of 2,4-dihydro-6-chloro-5(7)-methyl-7(5)-phenyl-1H-1,4-diazepine•HCIO^ (1.4 mmol) in acetonitrile (5 mL) was was added to a mixture of the potassium salt of 5-chloropyrimidine-2-thione (1.4 mmol) in acetonitrile (20 mL), and the resulting mixture was heated under reflux for 3 h. The solid material was then removed by filtration with water,

the water as well as the solid residue was extracted with ethyl acetate, the dried (MgSO 4 ) ethyl acetate solution was evaporated and the residue was recrystallized from dilute MeOH; yield 66%, sm.p. 222°C.

1H NMR (acetone-D,) 6 2.6 (Me), 4.1 (CH„CH_), 7.3 (Ph), 8.60

(H-4, H-6).

Example 34

2- ( 2, 4- dihydro- 5( 7)- methyl- 7( 5)- phenyl- 1, 4- diazepine- 6- methyl1)-thio- 5- chloropyrimidine• HC1

a) 2, 4- dihydro- 6- chloromethyl- 5( 7)- methyl- 7( 5)- phenyl- 1H- 1, 4-diazepine • HCIO^

Paraformaldehyde (7 mmol) was added to a solution of ■ 1H-2,4-dihydro-5(7)-methyl-7(5)-phenyl-1,4-diazepine-HCIO^

(5.2 mmol) in concentrated HG1 (10 mL). The mixture was stirred at room temperature for 15 minutes before the product was filtered off; yield 1.30 g....

<1>H NMR (acetone-db ,): δ 2.7 (Me), 3.9 (CH0 Z CH 2 „), 4.4 (CH„ ZC1),

7.5 (Ph.D.).

b) 2-( 2, 4- dihydro- 5( 7)- methyl- 7( 5)- phenyl- 1H- 1, 4- diazepin-6- methyl 1) thio- 5- chloropyrimidine • HC1

5-Chloropyrimidine-2-thione (2 mmol) and triethylamine (0.28 mL, 2 mmol) were stirred together in dichloromethane (20 mL) until all the material was dissolved. N-(1H-2,4-dihydro-6-chloromethyl-5(7)-methyl-7(5)-phenyl-1H-1,4-diazepine-HClO4 (0.68 g, 2 mmol) was then added , the mixture was heated under reflux for 1 hour, the solvent was distilled off, the residue triturated with water, the insoluble material extracted with CHCl^EtOAc, the dried (MgSO^) organic solution evaporated and the residue recrystallized from EtOAc:acetone:petroleum ether:

yield 69%, sm.p. 225°C

<1>H NMR (acetone-dg): <5' 2 , 6 (Me), 3.9 (CHCH 2 ), 4.0 (CH 2 S ), 7.5 (Ph), 8.50 (H-4, H-6).

Example 35

2-(pyrimidine-2-y1)thio-5-bromopyrimidine

2-Chloro-5-bromopyrimidine (10 mmol) was added to a solution of pyrimidine-2-thione (10 mmol) in ethanolic 0.24M NaOEt (45 ml), the mixture was heated under reflux for 2 h, the solvent distilled off , the residue extracted with chloroform (70 ml), the chloroform solution shaken with 2M NaOH and water, the dried (MgSO 4 ) solution evaporated and the residue repeatedly extracted with petroleum ether to give the title compound. Yield 35%, sm.p. 178-180°C (iPrOH).

<1>H NMR (CDCl3): δ 7.13 (H-5<1>), 8.60 (H-4', H-6'), 8.66 (H-4, H-6).

Example 36

2-(2-thienylmethoxycarbonylmethyl)thio-4,6-dimethyl-5-bromopyrimidine

a) 2-thienylmethyl-bromoacetate:

A solution of bromoacetyl chloride (60 mmol) and 2-hydroxymethylthiophene (60 mmol) in benzene (100 mL) was heated under reflux for 90 min, the cold solution was shaken with saturated aqueous NaHCO^, the dried (MgSO^) - the solution was evaporated and the residue was fractionally distilled;

dividend 48%, k.p. 96°C/0.05 mmHg.

1 H NMR (CDCl 3 ) δ 3.80 (CH 2 ), 5.30 (OHCH 2 )-, 7.00 and 7.26 (thiophene).

b) 2-(2-thienylmethoxycarbonylmethyl)thio-4,6-dimethyl-5-bromopyrimidine

The above ester (6.6 mmol) was added to a mixture of 4,6-dimethyl-5-bromopyrimidin-2-thione•HCl (6 mmol) and triethylamine (15 mmol) in dichloromethane (50 mL), the mixture was stirred at room temperature for 1 day, more dichloromethane (50 ml) was added, the mixture was shaken with 1M NaOH and water (10 ml), the dried (MgSO 4 ) solution was evaporated and the residue was chromatographed on silica gel 60 (Merck, 25 g) using ether;

yield 80% of a pale yellow oil.

NMR. (CDCl 3 ) δ 2.46 (Ml), 3.86 (SCH 2 ), 5.26 (OCH 2 ), 6.96 and 7.23 (thiophene).

Example 37

2-(N-methylcarbamoyl)thio-5-chloropyrimidine

A mixture of 5-chloropyrimidine-2-thione (3 mmol) and methyl isocyanate (4 mmol) in dichloromethane (15 ml) was stirred at room temperature for 2 hours, the solvent was then distilled off and the residue was crystallized- from CHCl3:petroleum ether, yield 85%, sm.p. 115°C.

<1>H NMR (CDCl3 ) δ 3.03 (Me), 8.62 (H-4, H-6).

Example 38

2-( 2, 3, 5- tri- 0- benzoyl- 3- D- ribofuranosy1) thio- 5- chloropyrimidine • A mixture of 5-chloropyrimidine-2-thione (4.3 mmol), 2,3,5- tri-O-benzoyl-3-D-ribofuranosyl chloride (4.3 mmol) and triethylamine (4.3 mmol) in dichloromethane (25 mL) were stirred together at room temperature for 4 h, the mixture was evaporated and the residue triturated with water; the residue was the title compound, yield 28%.

<1>H NMR (CDCl 3 ): δ 4.75 (CH 2 ), 6.0-6.5 ( 4 H), 7.2-8.2 (3 Ph), 8.50 (H-4, H -6).

Example 39

2- methylsulfinyl- 5- chloropyrimidine

A solution of 2-methylthio-5-chloropyrimidine (13 mmol)

in chloroform (85 mmol) was cooled to -20°C and m-chloroperbenzoic acid (17 mmol) was added with stirring. The mixture was stirred for 40 minutes at -20°C and for 4 hours at 0°C and allowed to stand overnight at this temperature. The chloroform solution was then washed with 1M potassium carbonate (3 x 10 mL)

and the dried (MgSO 4 ) solution was evaporated. The remaining oily material crystallized on standing; yield 80%, sm.p. 48°C (n-heptane).

■ 4 NMR (CDCl 3 ): δ 2.93 (Me), 8.83 (2H-4.6).

Example 40

2-(2-thienylmethyl)sulfinyl-5-bromopyrimidine

85% m-chloroperbenzoic acid (1.5 mmol) was added to a solution of 2-(2-thienylmethylthio)-5-bromopyrimidine (1.5 mmol)

in dichloromethane (25 ml) at -10°C and the solution was allowed to stand at 0°C for 18 hours. The dichloromethane solution was then washed with saturated aqueous solutions of Na 2 SO 4 and NaHCO 3 , and the dried (MgSO 4 ) solution was evaporated to give the title compound; yield 53%, sm.p. 108-109°C (iPrOH).

<1>H NMR (CDCl 3 ) δ 4.53 (CH 2 , 6.9 (H-3", H-4'), 7.16 (H-5"), 8.83 (H-4, H- 6).

Example 41

2- benzylsulfinyl- 5- chloropyrimidine

Oxidation of 2-benzylthio-5-chloropyrimidine was carried out

using 1 molar equivalent of 85% m-chloroperbenzoic acid in dichloromethane, initially at -10°C and then at 0°C, as described in Example 40 above; yield 88%,

sm.p. 92°C (iPrOH).

1 H NMR (CDCl 3 ) δ 4.30 and 4.33 (CH 2 ), 7.23 (Ph), 8.73 (H-4, H-6).

Example 4 2

2-(iodomethyl)sulfinyl-5-chloropyrimidine

90% m-chloroperbenzoic acid (8.4 mmol) in chloroform (8 ml) was added dropwise over 10 minutes with stirring to a solution of 2-(iodomethyl)thio-5-chloropyrimidine in chloroform (7 ml) at -5 °C. The mixture was colored violet during the addition. The mixture was allowed to stand at room temperature overnight.

The chloroform solution was then extracted with 1M K 2 CO 3 , washed with a little water, and then the dried (MgSO 4 ) solution was evaporated and the product subjected to thick layer chromatography. 2-(Iodomethyl)sulfinyl-5-chloropyrimidine:

yield 24%, sm.p. 158°C,

IR (KBr): 1050 and 1090 cm"<1>(SO).

2-iodomethyl)sulfonyl-5-chloropyrimidine was formed as a by-product in a yield of 17%, m.p. 152°C.

Example 4 3

2-(chloromethyl)sulfinyl-5-chloropyrimidine

90% m-chloroperbenzoic acid (4.2 mmol) in chloroform (7 ml) was added dropwise over 40 minutes to a solution of 2-(chloromethyl)thio-5-chloropyrimidine (3.9 mmol) in chloroform (6 ml ) with stirring at -5°C. The mixture was allowed to warm to room temperature and stirred overnight, it was washed with 1M ^CO^, the dried (MgSO^) chloroform solution was evaporated and the residue was recrystallized from benzene/petroleum ether (60- 80°C); yield 73%, sm.p. 90°C.

"""ri .NMR (CDC1,): 6 4.70 and 5.00 (2 H-CH-SO, J 10 Hz), 8.84 3 ' -j'2gem (H-4, H-6) .

Example 4 4

2- ■( 4- Chlorophenoic Acid 1) Sulfinyl- 5- Chloropyrimidine

Method A: 85% m-chloroperbenzoic acid (1.76 mmol) was added to a solution of 2-(4-chlorophenoxymethyl)thio-5-chloropyrimidine (1.5 mmol) in dichloromethane (70 mL) at -10°C. The solution was allowed to stand at 0-5°C for 18 hours, after which it was concentrated and applied to a column of silica gel 60 (Merck, 25 g). Unreacted sulfide was eluted with diethyl ether and the sulfoxide with ethyl acetate; yield 51%, sm.p. 88-90°C.

•""H NMR (CDCl 3 ) 6 5 .28 and 5.33 (CH 2 ), 6.95 and 7.28 (PhH),

8.85 (H-4, H-6).

Example 45

2- methylsulfinyl- 5- bromopyrimidine

The title connection became . prepared by oxidation of 2-methylthio-5-bromopyrimidine with m-chloroperbenzoic acid in chloroform as described in Example 39; yield 90%, sm.p. 90°C (n-heptane).

<1>H NMR (CDCl 3 ): δ 2.91 (Me), 8.90 (H-4, H-6).

Example 4 6

2- benzylsulfinyl- 5- bromopyrimidine

Oxidation of 2-benzylthio-5-bromopyrimidine was carried out using a molar equivalent of 85% m-chloroperbenzoic acid in dichloromethane, first at -10°C and then at 0°C, as described in Example 40 above; yield 91%, sm.p. 101°C (iPrOH).

<1>H NMR (CDC1'3): δ 4 .26 and 4.31 (CH 2 ), 7.16 (Ph), 8.80

(H-4, H-6).

Example 4 7

2- phenylsulfinyl- 5- chloropyrimidine

30% hydrogen peroxide solution (0.8 g) was added to a solution of 2-phenylthio-5-chloropyrimidine (5 mmol) in acetic acid (4 ml) and allowed to stand at room temperature for 60 hours. The solution was then diluted (25 ml) and the precipitate was

purified by thick-layer (2 mm) chromatography on silica gel 60F (Merck). The plates were developed with EtOAc; yield 50%, sm.p. 115°C (naphtha).

"""H .NMR (CDCl 3 ) : δ 7.4 and 7.8 (Ph), 8.71 (H-4, H-6).

Example 4 8

2- allylsulfinyl- 5- chloropyrimidine

30% hydrogen peroxide (50 mmol) was added to a solution of 2-allylthio-5-chloropyrimidine (10 mmol) in acetic acid (15 mL) and the mixture was stirred at room temperature for 24 hours. , The resulting solution was concentrated under reduced pressure to a small volume, water (20 ml) was added, and the mixture was extracted with chloroform, the chloroform solution was washed with potassium carbonate solution, the dried (MgSO 4 ) solution was evaporated and the residue was crystallized from chloroform:

petroleum ether, yield 78%, m.p. 82°C.

<1>H NMR (CDCl3): δ 3.7-4.0 (CH2, 5.0-6.2 (3H, CH2<=>CH), 8.86

(H-4, H-6).

E xample 4 9

2-(5-chloropyrimidine-2-thiomethyl)sulfinyl-5-chloropyrimidine and 2-(5-chloropyrimidine-2-sulfinylmethyl)sulfonyl-5-chloropyrimidine

30% hydrogen peroxide (2 mL) was added to a solution of bis(5-chloropyrimidine-2-thio)methane (1.3 mmol) in acetic acid (10 mL) and the mixture was stirred at room temperature for 6 h. The mixture was then concentrated to a small volume under reduced pressure, water (20 mL) was added, the mixture was extracted with chloroform (3 x 20 mL), the dried (MgSO 4 ) chloroform solution was evaporated, the residue was extracted with acetone, the insoluble material was filtered off and recrystallized from DMSO; yield 22%, sm.p. 250°C. The product is. 2-(5-chloropyrimidine-2-sulfinylmethyl)sulfonyl-5-chloropyrimidine.

<X>HNMR (DMSO-d 6 /CDCl 3 ) : δ 5.31 and 5.63 "(CH 2 , d, J 14 Hz), 9.06 (H'-4, H'-6), 9.14 ( H-4, .H-6). IR (KBr): 1340, 1140 and 1130 (SO2), 1080 (SO)). The acetone solution from the extraction was evaporated, and the remaining 2-(5-chloropyrimidine-2-thiomethyl) sulfinyl-5-chloropyrimidine was crystallized from ethanol, yield 48%, mp 140°C.

<1>H NMR (CDCl 3 ): δ 4.73 and 4.93 (CH 2 , d, J 13 Hz), 8.56 (H'-4, H'-6), 8.81 (H-4, H-6). IR (KBr): 1080 cm"<1>(SO).

Example 50

2- propargylsulfiny1- 5- chloropyrimidine

.A mixture of selenium dioxide (4 mmol) and 35% H,,02 (4 mmol) in water (2.5 ml) was added to a solution of 2-propargylthio-5-chloropyrimidine in methanol (10 ml). The mixture was stirred at room temperature for 18 h before water (50 mL), saturated with NaCl was added and the mixture was extracted with chloroform (3 x 20 mL). The dried (MgSO 4 ) chloroform solution was evaporated and the residue recrystallized from chloroform: petroleum ether; yield 63%, sm.p. 92°C.

■ 1H NMR (CDCl 3 ): δ 2.28 (HC= t,"J 2 Hz), 3.87 and 4.09 (CH 2 ,

J 15 Hz), 8.85 (H-4, H-6), IR (KBr): 3235 (CH = ), 2110 and

2100 (-.C=C-). MS [70 eV, m/e (% rel. int..)]: 200 (13, M)

199 (19), 173 (33), 171 (100), 146 (25), 114 (30V 113 (31),

111 (47).

Example 51

2-(2,3-epoxypropyl)sulfinyl-5-chloropyrimidine

A mixture of 35% ^ 2°2 ^1/9 mino1)°9Se02^1'9 mm°D

in water (1.5 mL H 2 O) was added to a solution of 2-(2,3-epoxypropyl)thio-5-chloropyrimidine (1.9 mmol) in methanol (7 mL). The mixture was stirred at room temperature for 4 h before saturated aqueous NaCl (30 mL) was added and the mixture was extracted with chloroform (3 x 15 mL). The dried (MgSO₂) chloroform solution was evaporated and the residue was purified by preparative TLC on silica gel using CHCl₂:

EtOH (95:5), yield 24%, m.p. 92°C.

1 H NMR (CDCl 3 ): δ 2.4-3.6 (5H, m), 8.84 (H-4, H-6).

IR (KBr): 1050 cm"<1>(SO).

Example 52

2-(2-hydroxy-3-chloropropyl)sulfinyl-5-chloropyrimidine

A solution of 35% ^ 2^ 2 (1.7 mm°l)°9^e°2^>^ mmol)

in water (2.5 ml) was added to a solution of 2-(2-hydroxy-3-chloropropyl)thio-5-chloropyrimidine (1.7 mmol) in methanol (10 ml). The mixture was stirred at room temperature for 18 hours before

saturated aqueous NaCl (40 mL) was added and the mixture was extracted with chloroform (3 x 20 mL). The dried (MgSO 4 ) chloroform solution was evaporated and the residue was crystallized from ethyl acetate; yield 59%, sm.p. 170°C.

1IH R N(MKR Br)(D: MS3O40-0 d6 ,)(O:' H6 ), 31,00-604-,14 07(0 6Hc, m m-1) , (S9O,1)0 .(H -<4,>H-6) .

Example 53

2-[ 3-( 1- perhydroazocinyl) propyl] sulfinyl- 5- chloropyrimidine

A solution of SeO,, (1.3 mmol) and 35% H2O,, (1.3 mmol)

in water (2 mL) was added to a solution of 2-[3-(perhydrd-azocinyl)propyl]thio-5-chloropyrimidine (1.3 mmol) in methanol (10 mL), the resulting solution was stirred at room temperature, overnight, saturated aqueous NaCl solution was added, the mixture was extracted with chloroform (10 x 15 ml), the dried (MgSO 4 ) chloroform solution was evaporated and the residue was thoroughly washed with acetone, yield: 44%, m.p. . 160 C.

<1>H NMR (DMSO-d6/CDCl3): δ 1.4-1.6 and 2.9-3.5 (10 x CH2)V 9.0

(H-4, H-6). IR (KBr): 1080 cm"<1>(SO).

Example 54

2- iodomethylsulfony1- 5- chloropyrimidine

90% m-chloroperbenzoic acid (8.4 mmol) in chloroform (8 mL)

was added dropwise with stirring during a<y>10 minutes to a solution of 2-iodomethylthio-5-chloropyrimidine in chloroform

(7 mL) at -5°C. The reaction mixture was colored violet during the addition. The mixture was allowed to stand overnight at room temperature. The chloroform solution was then extracted with 1M K 2 CO 2 , washed with a little water, and the dried (MgSO 2 ) solution was evaporated and the product subjected to thick layer chromatography. 2-(Iodomethyl)sulfonyl-5-chloropyrimidine was obtained in a yield of 17% (together with 2-(iodomethyl)-sulfinyl-5-chloropyrimidine).

Example 55

2-(chloromethyl)sulfonyl-5-chloropyrimidine

90% m-chloroperbenzoic acid (9.4 mmol) in chloroform (9 mL)

was added dropwise over 30 minutes to a solution of 2-(chloromethyl)thio-5-chloropyrimidine (4.2 mmol) in chloroform (6 ml) with stirring at -5°C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was then washed with 1M 2 CO 3 , the dried (MgSO 4 ) chloroform solution was evaporated and the residue recrystallized from ethanol; yield 63%, sm.p. 100°C.

1 H NMR (CDCl 3 ): δ 5.02 (2 H-CH 2 ), 8.88 (H-4, H-6).

Example 56

Diethyl-(5-chloropyrimidine-2-sulfonyl)methanephosphonate

90% m-chloroperbenzoic acid (8 mmol) was added dropwise with stirring over 5 minutes to a solution of diethyl-(5-chloropyrimidine-2-thio)methanephosphonate (2.7 mmol) in chloroform (15 mL) at -5 °C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then extracted with 1M 2 CO 2 , the chloroform solution was dried (MgSO 2 ), the solvent was evaporated and the residue was recrystallized from benzene:petroleum ether (60-80°C), yield 90%, m.p. 119°C.

1 H NMR (CDCl 3 ): δ 1.38 (6H, 2Me), 3.9-4.5 (6H, 2 OCH 2 and CH 2 P), 8.92 (H-4, H-6).

Example 5 7

2-allylsulfony1-5-chloropyrimidine

m-chloroperbenzoic acid (90%, 6 mmol) was added to a solution of 2-allylthio-5-chloropyrimidine (2.3 mmol) in chloroform

(10 ml) and the mixture was stirred at 40°C for 90 minutes. The cold reaction mixture was extracted with aqueous potassium carbonate, the chloroform solution was dried (MgSO 4 ), the solution was evaporated and the residue was crystallized from methanol; yield 70%, sm.p. 84°C.

1 H NMR (CDCl 3 ): 6 4 , 24 (CH 2 , J 7 Hz), 5.1-6.2 (CH=CH 2 ), 8.90 (H-4 , H-6).

Example 5 8

1-(3-oxobuten-1-yl)sulfonyl-5-chloropyrimidine

90% m-chloroperbenzoic acid (11.5 mmol) in chloroform (10 mL)

was added to a solution of 2-(3-oxobuten-1-yl)thio-5-chloropyrimidine in chloroform (10 ml) and the mixture was stirred at 40°C

for 2 hours. The cold reaction mixture was extracted with aqueous KHCO 4 , and the dried (MgSO 4 ) chloroform solution was evaporated; yield 92%. The cis/trans isomers could be separated by thick layer chromatography (silica gel, CHCl :EtOAc (1:1)). (E): sm.p. 117 C (MeOH). H NMR (acetone-dg): 6 2.4 3 (Me), 7.12 and 7.6 8 (Ha, HP, d, J 16Hz), 9.10 (H-4, H-6),

(Z): sm.p. 95°C (MeOH). 1 H NMR (acetone-db,): δ 2.32 (Me), 6.97 and 7.13 (Ha,'HP, d, J 12 Hz), 9.10 (H-4, H-6).

Example 59

2-(1,2-propadienyl)-sulfonyl-5-chloropyrimidine

90% m-chloroperbenzoic acid (13 mmol) in chloroform (20 mL)

was added dropwise over 30 minutes to a solution of the isomeric 2-propargylthio-5-chloropyrimidine and 2-(1,2-propadienyl)-thio-5-chloropyrimidine (3.5 g; ratio 3:2) in chloroform (30 ml) with stirring at -5°C. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then washed with 2M K 2 CP 3 , the dried (MgSO 4 ) chloroform soln.

was evaporated and the residue crystallized from methanol. The yield of 2-(1,2-propadienyl)sulfonyl-5-chloropyrimidine was 74%,

sm.p. 130°C. Under the conditions of oxidation with m-chloroperbenzoic acid, the propargyl isomer was completely isomerized to the allene isomer.

1H NMR (acetone-d,): 6 5 , 65 (CH, t, J 6 Hz), 6.73 (CH, t, J 6.Hz),

6 9.04 (H-4, H-6, p). IR (KBr): 1960 and 1920 (allene), 1330 and 1140 (S02).

Example 60

2-(2-thienylmethylsulfonyl)-5-bromopyrimidine

A solution of 2-(2-thienylmethylthio)-5-bromopyrimidine

.(3 mmol) and 85% m-chloroperbenzoic acid (9 mmol) in dichloromethane

(80 ml) was allowed to stand at room temperature for 1 day. The solution was then washed with saturated Na 2 SO 3 (3 x 15 mL), washed with saturated NaHCO 3 (3 x 10 mL) and the dried (MgSO 4 ) dichloromethane solution was evaporated to give the title compound;, yield 70%, m.p. . 124-126°C (iPrOH).

<1>H NMR (CDCl 3 ): δ 4.93 (CH 2 , 6.9 (H-3', H-4'), 7.20 (H-5'), 8.93 (H-4, H -6).

Example 61

2- f enacylsulf ony 1- 5- bromopyrimidine'

- 2-phenacylthio-5-bromopyrimidine was oxidized to the sulfone

using m-chloroperbenzoic acid as described in Example 61, yield 91%, m.p. 95°C (iPrOH).

1 H NMR (CDCl 3 ): δ 5.16 (CH 2 ), 7.5-7.8 (Ph), 8.92 (H-4, H-6).

Example 62

2- benzylsulfonyl- 5- bromopyrimidine

A solution of 2-benzylthio-5-bromopyrimidine (10.6 mmol)

and 85% m-chloroperbenzoic acid (31.8 mmol) in dichloromethane (200 ml) was allowed to stand at room temperature for 3 days before the reaction mixture was worked up as described in Example 61 above;

yield 93%, sm.p. 142-143°C (iPrOH).

1 H NMR (CDCl 3 ): δ 4.73 (CH 2 ), 7.26 (Ph), 8.90 (H-4, H-6).

Example 6 3

2-(2-thienyl)sulfony1-5-chloropyrimidine

A solution of 2-(2-thienyl)thio-5-chloropyrimidine (6 mmol) and 85% m-chloroperbenzoic acid (15.3 mmol) in dichloromethane (1.50 ml) was allowed to stand at room temperature for 2 days. Additional dichloromethane (100 mL) was then added, the solution was shaken with saturated aqueous Na 2 SO 3 (3 x 20 mL), with saturated aqueous NaHCO 3

(2 x 20 mL), the dried (MgSO 4 ) solution was evaporated

and the residue was crystallized from ethanol; yield 90%,

sm.p. 116-117°C.

<1>H NMR (CDCl 3 ): δ 7.1-7.8 (thiophene), 8.80 (H-4, H-6).

Example 6 4

2- benzylsulfonyl- 4, 6- dimethyl- 5- bromopyrimidine

A solution of 2-benzylthio-4,6-dimethyl-5-bromopyrimidine (5 mmol) and 85% m-chloroperbenzoic acid (15.9 mmol) in dichloromethane (100 ml) was allowed to stand at room temperature for 3 days. The solution was then shaken with saturated aqueous Na 2 SO 3 (3 x 15 mL), saturated aqueous NaCH0 3 (3 x 10 mL), and the dried (MgSO 4 ) solution was evaporated to give the sulfone; yield 94%, sm.p. 138-139°C (iPrOH) .•

<1>H NMR (TFA) : δ 2.83 (Me), 4.93 (CH 2 ), 7.33 (Ph).

Example 6 5

2-(carbamoylmethyl)sulfonyl-4,6-dimethyl-5-bromopyrimidine

A solution of 2-(carbamoylmethyl)thio-4,6-dimethyl-5-bromopyrimidine (2.16 mmol) and 85% m-chloroperbenzoic acid (6.48 mmol) in dichloromethane (75 mL) was allowed to stand at room temperature for 3 days. The solution was then shaken with saturated aqueous Na 2 SO 3 , saturated aqueous NaHCO 3 and the dried (MgSO 4 ) solution was evaporated to give the sulfone; yield 72%, sm.p. 175-177°C (iPrOH).

<1>H NMR' (DMSO- dg ) : δ 2.50 (Me), 3.80 (CH 2 ).

Example 6 6

2- phenylsulfonyl- 5- chloropyrimidine

30% hydrogen peroxide solution (2 g) was added to a solution of 2-phenylthio-5-chloropyrimidine (18 mmol) in acetic acid (14 ml). After 2 days at room temperature, an additional 2 g of 30% hydrogen peroxide solution was added, and the resulting solution was heated at 50°C for 4 hours. The sulfone was precipitated by diluting the cold solution (100 mL); yield 80%, sm.p. 103°C (EtOH).

<1>H NMR (CDCl 3 ): <5 7.6 and 8.1 (Ph, m) 8.83 (H-4, H-6).

Example 6 7

Phenylsulfonyl-5-bromopyrimidine

2-phenylthio-5-bromopyrimidine (prepared as described for oxidation with hydrogen peroxide of the chlorine analogue in example 43, yield 75%, m.p. 103°C (iPrOH).

<1>H NMR (CDCl 3 ): δ 7.6 and 8.1 (Ph, m), 8.90 (H-4, H-6).

Example 6 8

2- methylsulfony1- 4- methoxycarbonyl1- 5- chloropyrimidine

A solution of 2-methylthio-4-methoxycarbonyl-5-chloropyrimidine (10 mmol) in 30% hydrogen peroxide (2.5 g) in acetic acid (8 ml) was allowed to stand at room temperature for 3 days. The mixture was then poured onto ice, neutralized with sodium bicarbonate and extracted with chloroform, and the chloroform solution was evaporated. The oily residue crystallized slowly on standing; yield 74%, sm.p. 96°C (EtOH).

1 H NMR (CDCl 3 ): δ 3.38 (SO 2 Me), 4.06 (OMe), 7.91 (H-6).

Example 6 9

2- methylsulfony1- 4- N, N- diethylaminocarbonyl- 5- bromopyrimidine

Chlorine was introduced into an ice-cold suspension of 2-methylthio-4-N,N-diethylaminocarbonylpyrimidine' (15 mmol) in water (70 ml) for approx. 6 minutes with vigorous stirring. After stirring for 30 minutes in the ice bath, chlorine was again passed through the mixture for approx. 6 minutes. After stirring for a further 20 minutes, the mixture was neutralized with sodium bicarbonate, extracted with chloroform, the chloroform solution washed and dried (MgSO 4 ) and the solvent

distilled; 'yield 86%, sm.p. 141°C (iPrOH).

^ NMR (CDCl 3 ): δ 1.23 and 3.13/3.61 (NEt 2 ), 3.33 (SC 2 Me),

9.08 (H-6).

Example 70

2-benzylsulfonyl-5-chloropyrimidine

A solution of 2-benzylthio-5-chloropyrimidine (3.7 mmol)

and potassium permanganate (5.2 mmol) in 1N acetic acid (12 mL) was kept at room temperature until TLC (silica gel with EtOAc) showed complete oxidation (ca. 30 min.). The mixture was then diluted and neutralized with sodium bicarbonate. The precipitate was collected by filtration, sucked dry and

washed with chloroform. The chloroform wash was used to extract the aqueous filtrate and the chloroform solution was washed with a little water, dried (MgSO 4 ) and evaporated. Yield 30%, sm.p. 122-124°C (iPrOH).

"""H NMR (CDC.13): ? 4 , 75 (CH 2 ), 7.28 (Ph), 8.83 (2 H-4.6).

Example 71

2- ( 2, 3, 4, 6- tetraacetylglucopyranosyl) sulfony1- 5- chloropyrimidine 2-( 2,3,4,6-tetraacetylglucopyranosyl) thio-5- chloropyrimidine•

(1.0 mmol) was dissolved in acetic acid (10 mL) and a solution of KMnO 4 (1.5 mmol) in water (5 mL) was added. The mixture was stirred at 40°C and additional amounts of KMnO^ (3 x 0.15 g, 0.9 mmol) were added at intervals of 2.5 hours, 1 day, 2 days and 1 day, and after another 1 day the reaction was stopped. An aqueous solution of NaIlSO 3 was then added until all the MnO 2 had dissolved and the product was precipitated by addition of water and crystallized from EtOH; dividend 30%,

sm.p. 180°C.

<1>H NMR (CDCl 3 ): δ 1.8-2.0 (Ac), 3.5-6.0 (glucose), 8.90

(H-4, H-6).

Example 72

2-( 5- chloropyrimidine- 2- oxymethyl) sulfonyl- 5- chloropyrimidine

The molybdenum complex MoO^•HMPA•H2O (1.9 mmol) was added to a solution of 2-(5-chloropyrimidine-2-oxymethyl)thio-5-chloropyrimidine (0.76 mmol) in dichloromethane, (10 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then washed with water (30 mL), the washings were extracted with chloroform, the combined chloroform solutions were extracted with 1M K 2 GO 3 , the dried (MgSO 4 ) chloroform solution was evaporated and the residue was crystallized from chloroform:

petroleum ether; yield 48%, sm.p. 135°C.

<X>H NMR (CDCl 3 ): δ 6.03 (CH 2 ), 8.41 (H'-4, H'-6), 8.86 (H-4,

h-6).

Example 73

2-(iodomethyl)sulfony1-5-chloropyrimidine

MoO 5 HMPA H 2 O (5 mmol) in dichloromethane (15 mL) was added

to a solution of 2-(iodomethyl)-thio-5-chloropyrimidine (2 mmol)

in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 days before washing with water. The washings were extracted with dichloromethane (3 x 15 mL), and the combined dichloromethane solutions were washed with 1M K 2 CO 3 , the dried dichloromethane (MgSO 4 ) was evaporated and the residue was recrystallized from ethanol: yield 52%, m.p. 152°C.

<X>H NMR (CDCl 3 ): δ 4.89 (CH 2 ), 8.90 (H-4, H-6).

E xample 7 4

2-(4-tolylsulfonyl)-5-bromopyrimidine

A mixture of 2-chloro-5-bromopyrimidine (3.6 mmol), p-'t<q>luensulfinic acid Na salt (6 mmol), TEBA (6 mmol) and LiBr (1.0 g) in EtOH ( 30 ml) was heated under reflux

for 20 hours until TLC monitoring (silica gel/benzene) showed complete conversion. The solvent was removed under reduced pressure, water (25 mL) was added to the residue,

the aqueous solution was allowed to stand at 0°C and the precipitate was collected and extracted with chloroform. Evaporation of the chloroform solution gave the title compound; dividend 22%,

sm.p. 142-144°C (iPrOH).

1 H NMR (CDCl 3 ): δ 2 .43 (Me), 7.30 and 7.96 (Ph), 8.90. (H-4, H-6).

Example 75

2- ( 4- tolyl) sulfonyl- 5- iodopyrimidine- •

A mixture of 2-chloro-5-iodopyrimidine (7.5 mmol), p-toluenesulfinic acid Na salt (12.1 mmol) and catalytic amounts

of iodine and Cu powder in ethanol (90 mL) was heated under reflux for 3 days. The solvent was then distilled off, the residue was extracted with chloroform, the chloroform solution was washed with saturated aqueous NaHCO 3 and the dried (MgSO 4 ) solution was evaporated to give the sulfone; dividend 10%, sm.p. 138-139°C (iPrOH).

1 H NMR (CDCl 3 ): δ 2 .43 (Me), 7.30. and 7.93 (Ph), 9.02 (H-4, H-6)'.

Example 76

2-( 4- tolyl) sulfonyl- 4, 6- dimethyl- 5- bromopyrimidine

A mixture of 2-chloro-4,6-dimethyl-5-bromopyrimidine

(5 mmol), p-toluenesulfinic acid Na salt (8.3 mmol) and catalytic amounts of iodine and Cu powder in ethanol (60 mL) were heated under reflux for 3 days. The solvent was then distilled off, the residue was extracted with chloroform (100 mL), the chloroform solution was washed with aqueous saturated NaHCO 3 and the dried (MgSO 4 ) solution was evaporated to give

give the sulfone; yield 23%, sm.p. 157-158°C (iPrOH).

<1>H. NMR (DMSO-dg): 6 2 , 4 3 (Me.-Ph), 2.6 3 (4-Me, 6-Me), 7.4 3 and 7.86- (Ph).

Example 77

2-(trans-styryl)sulfonyl-5-chloropyrimidine

A sodium hydride dispersion (55-60%, 2 mmol) was further dispersed in benzene (4 mL) and added gradually to a solution of diethyl 1-(5-chloropyrimidine-2-sulfonyl)methanephosphonate (0.66 g,

2 mmol) in benzene (4 mL). The mixture was stirred for 10 minutes

before a solution of benzaldehyde (0.21 g, 2 mmol) in benzene (2 ml) was added. The resulting mixture was stirred at room temperature overnight before extraction with water. Evaporation of the dried (MgSO4) benzene solution gave the product which was recrystallized from ethanol; yield 0.20 g 35%, m.p. 150°C.

<1>H NMR (CDCl J: δ 7.24 and 7.90 (2 H-vinyl, J . 16 Hz), 7.60

3 3 ' vic

(Ph, m) , 8.90 (2H-4.6).

Example 78

2-(2,2'-furylvinyl)sulfony1-5-chloropyrimidine

A sodium hydride dispersion (55-60%, 0.084 g, 2 mmol). was added to ethylene glycol dimethyl ether (4 mL) and the mixture was gradually added to a solution of diethyl-(5-chloropyrimidine-2-sulfonyl)methanephosphonate (0.66 g, 2 mmol). The mixture was stirred for 10 minutes before a solution of furfural (0.19 g, 2 mmol) in ethylene glycol dimethyl ether (2 mL) was added. The resulting mixture was stirred at room temperature overnight. The insoluble material was then removed by filtration, the filtrate evaporated to dryness and the residue crystallized from ethanol; yield 0.14 g', 26%, m.p. 140°C.

<1>H NMR (CDCl 3 ) : <5 6.4-7.8 (2 H-vinyl, 3 H-furyl, m), 8.90

(2H-4, 6) .

Example 79

2-(5-nitro-2-thienyl)sulfonyl-5-chloropyrimidine

A solution of 2-(5-nitro-2-thienyl)thio-5-chloropyrimidine (1.2 mmol) and 85% m-chloroperbenzoic acid (3.06 mmol) in dichloromethane (30 mL) was allowed to stand at room temperature for 1 day . The solution was then diluted with dichloromethane (50 mL), the solution was shaken with saturated aqueous Na 2 SO 3 (3 x 10 mL) and then with saturated aqueous NaHCO 3 (2 x 10 mL) and the dried (MgSO 4 ) solution was evaporated and the solid residue recrystallized from EtOH; yield 60%, sm.p. 144-146°C.

1 H NMR. (CDCl 3 ) : δ 7.71 and 7.88 (H-3<1>, H-41), 8.85 (H-4, H-6).

Example 80

2-[N-(2-tolyl)carbamoylmethyl)sulfonyl-4,6-dimethyl-5-bromo-pyrimidine

A solution of 2-[N-(2-tolyl)carbamoylmethyl)thio-4,6-dimethyl-5-bromopyrimidine (35 mmol) and 85% m-chloroperbenzoic acid

• (10.5 mmol) in dichloromethane (120 ml) was allowed to stand at room temperature for 3 days. The mixture was then shaken with saturated aqueous Na 2 SO 3 (3 x 15 mL) and then with saturated aqueous Na 1 CO 3

(2 x 10 ml) and the dried solution was evaporated;

yield 85%, sm.p. 144°C.

^ NMR (CDCl 3 ): δ 2.23 (2'-Me), 2.7 (Me 2 ), 4.53 (CH 2 ).

Example etc

2- phenylsulfony1- 5- fluoropyrimidine

2-Phenylthio-5-fluoropyrimidine (4 mmol) was dissolved in acetic acid (5 mL), 30% H 2 °2 (5 mL) was added, and the resulting solution was stirred at room temperature for 3 days. The product was precipitated by the addition of ice-cold water (35 ml); yield 71%, sm.p. 105°C (iPrOH).

5 NMR (CDCl 3 ): <S 7.5-8.1 (Ph), 8.65 (H-4, H-6).

Example 82

2-(2-thienylmethoxycarbonylmethyl)sulfonyl-4,6-dimethyl-5-bromopyrimidine

A solution of 2-(2-thienylmethoxycarbonylmethyl-thio-4,6-dimethyl-5-bromopyrimidine (4.8 mmol) and 85% m-chloroperbenzoic acid (14.4 mmol) in dichloromethane (100 ml) was allowed to stand at room temperature in 2 days, more dichloromethane (50 mL) was added, the solution was shaken with saturated aqueous Na 2 SO 3 (3 x 20 mL) and with saturated NaHCO 3 (2 x 10 mL), and the dried (M<g>SO 4 ) solution was evaporated; yield 44%, mp 87-88 C (EtOAc/Et 2 O).

:H NMR (CDCl 3 ): δ 2 .65 (Me), 4.56 (SO 2 CH 2 ), 5.20 (OHCH 2 ), 6.90/6.93, 7.25 (thiophene).

Claims (9)

1. Analogy method for the preparation of physiologically active compounds with the formula where X means a halogen atom; n is 0, 1 or 2; 12 R and R , which may be the same or different, each mean a hydrogen atom or a carboxyl, esterified carboxyl, amido or mono- or di-C 1 -4 alkylamido group or a C 1 -4 alkyl group; and R means a C.^_32 saturated or unsaturated, linear or branched, cyclic or acyclic aliphatic group or an araliphatic or heterocyclic substituted aliphatic group, a heterocyclic group or an aryl group, which groups may optionally carry one or more substituents selected from halogen atoms and oxo -, nitro-, hydroxy-, etherified hydroxy-, esterified hydroxy-, primary, secondary or tertiary amino-, acylamino-, etherified mercapto- or -SO- or -SO2" derivatives thereof and esterified phosphonic acid groups, with the proviso that R 3 is not an unsubstituted alkyl, aralkyl or aryl group other than a phenyl or benzyl-12 group when R and/or R is hydrogen or a C 1 -4 alkyl group and X means a fluorine, chlorine or bromine atom, with the further proviso that R 3 is. different from a methyl group etc. 2 when R is a carboxyl group, R is a hydrogen atom and X is a chlorine or bromine atom, and when an acidic or basic group is present, the physiologically compatible salts thereof, characterized , by ata) for the preparation of compounds of formula I where n is 2, a compound of the formula is oxidized: 12 3 where R , R , R and X are as stated above, and m is 0 or 1; b) for the preparation of a compound of formula I where n is 1, a compound of the formula is oxidized: 12 3 where R , R , R and X are as indicated above; c) for the preparation of compounds of formula I where n is 2, a compound with the formula is reacted: 12 where R , R and X are as indicated above, and Y means an outgoing havtoom r R e3lleer r sgorm uppaneg, imtet d doveen nsfourlf, ineslylerr e meet d safolrt mdeelern avR ;3SO„H,d) for the preparation of compounds of formula I where n is 0, 1 or 2, and R 3 means a vinyl group of the formula 4 5 6 where R , R and R , which may be the same or different, each means a hydrogen atom or a C 1-6 alkyl group, an aralkyl group, a heterocyclic alkyl group, an aryl group or a heterocyclic group, which groups may optionally be substituted as indicated above, reacts a compound with the formula: 7 4 8 9 where R means the group -CHR -P(0)R R or 4 8 9 10 where R is as indicated above, and R , R and R , which may be the same or different, each mean an aryl or alkoxy group, with a compound of the formula: where R^ and R^ are as stated above;- - e) for the preparation of compounds of formula I where n is 0, a compound with the formula is condensed: where R 3 is as indicated above, or an acid addition salt. hence, with a compound of the formula: 12 where R , R and X are as stated above, or a functional derivative thereof; f) for the preparation of compounds of formula I where n is 0, a compound of the formula is reacted: 12 where R , R and X are as above, and Y means an out walking atom or group, with a thiol of the formula R 3SH or a thiolate of the formula: where R 3 is as indicated above, M means a stabilizing cation, and n means the cation's charge; g) for the preparation of compounds of formula I where n is 0, a compound with the formula is reacted: 12 wherein R , R , and X are as defined above, with a reagent serving to alkylate the sulfur atom to add a group R <3> thereto; and optionally a prepared compound of formula I in which an acidic or basic group is present is converted into a salt thereof. 2. Process as stated in claim 1 for the production of 2-(chloromethyl)sulfony1-5-chloropyrimidine, characterized by the fact that output 12 3 is used materials where R and R are each hydrogen, R is chloromethyl, n is 2 and X is chlorine, or they are converted to said meanings. 3. Process as stated in claim 1 for the production of 2-styrylsulfonyl-5-chloropyrimidine, characterized in that starting materials are used where R 1 and R 2 are each hydrogen, R 3 is styryl, n is 2 and X is chlorine, or the converted into the aforementioned meanings.. 4. Process as stated in claim 1 for the production of 2-benzylsulfony-1-5-chloropyrimidine, characterized 1 2 in that starting materials are used where R and R are each 3 hydrogen, R is benzyl, n is 2 and X is chlorine, or they are converted to said meanings. 5. Process as stated in claim 1 for the production of 2-(3-oxobuten-1-yl)sulfonyl-5-chloropyrimidine, characterized in that starting materials are used where R and R are each hydrogen, R is 3- oxobutene- 1-yl, n is 2 and X is chlorine, or they are converted to said meanings. 6. Process as stated in claim 1 for the production of 2-(iodomethyl)sulfony1-5-chloropyrimidine, characterized in that the starting material 12 3 is used materials where R and R are each hydrogen, R is iodomethyl, n is 2 and X is chlorine, or they are converted to said meanings. 7. - Process as stated in claim 1 for the production of 2-benzylsulfonyl-5-bromopyrimidine, characterized in that starting materials are used where R and R <2> are each hydrogen, R <3> is benzyl, n is 2 and X is bromine, or they are converted to the aforementioned meanings. 8. Process as set forth in claim 1 for the production of 2-(5-chloropyrimidine-2-oxymethyl)sulfony1-5-chloropyrimidine, characterized in that output.s-12 3 materials are used where R and R are each hydrogen, R is 5-chloropyrimidine-2-oxymethyl), n is 2 and X is chlorine, or they are converted to the aforementioned meanings. 9. Process as stated in claim 1 for the production of 2-benzylsulfinyl-5-chloropyrimidine, characterized in that starting materials are used where R 1 and R <2> are each hydrogen, R 3 is benzyl, n is 1 and X is chlorine, or they are transformed into said meanings.